A large number of cytokines participate in the inflammatory response, including IL-1, IL6, IL-8 and TNF-α Overproduction of cytokines such as IL-1 and TNF-α are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others (Henry et al., Drugs Fut. 24:1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6:807-823 (1999)). Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, a monoclonal antibody to TNF-α (Remicade) (Rankin et al., Br. J. Rheumatol., 34:334-342 (1995)), and a soluble TNF-α receptor-Fc fusion protein (Etanercept) (Moreland et al., 25 Ann. Intern. Med., 130:478-486 (1999)).
The biosynthesis of TNF-α occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-α production are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinases. These kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes.
There are four known isoforms of p38, i.e., p38α, p38β, p38γ, and p38δ. The α and β isoforms are expressed in inflammatory cells and are key modulators of TNF-α production. Inhibiting the p38α and β enzymes in cells results in reduced levels of TNF-α expression. Also, administering inhibitors of p38α and β in animal models of inflammatory disease has proven that such inhibitors are effective in treating those diseases. Accordingly, the p38 enzymes serve an important role in inflammatory processes mediated by IL-1 and TNF-α. See, e.g., U.S. Pat. Nos. 6,277,989, 6,130,235, 6,147,080, 5,945,418, 6,251,914, 5,977,103, 5,658,903, 5,932,576, and 6,087,496; and in International Patent Application Publication Nos. WO 00/56738, WO 01/27089, WO 01/34605, WO 00/12497, WO 00/56738, WO 00/12497 and WO 00/12074. See also, U.S. Pat. Nos. 6,376,527; 6,316,466 and 6,444,696; and International Patent Application Publication Nos. WO 99/57101, WO 02/40486, WO 03/032970, WO 03/033482, WO 03/032971, WO 03/032986, WO 03/032980, WO 03/032987, WO 03/033483, WO 03/033457 and WO 03/032972.
Thus, there is a need for inhibitors of p38 kinases, including p38α and p38b kinase, for treatment, prevention, or amelioration of one or more symptoms of diseases and disorders associated with p38 kinase activity.